The present invention relates to methods and compositions for the direct catalytic asymmetric aldol reaction of aldehydes with ketones or nitroalkyl compounds.
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Few chemical reactions have reached the prominence of aldol-type reactions in the synthesis of complex molecules (Mukaiyama, 1982; Kim et al., 1991; Heathcock, 1984). The classical aldol reaction is highly atom economic (Trost, 1995) but suffers from poor chemo- and regioselectivity. In current practice, aldol reactions typically employ a preformed enolate, enol, or equivalent; an example is the Mukaiyama reaction, which employs an enol silyl ether. These reactions generally provide greater selectivity, but require stoichiometric amounts of base and/or adjunct reagents (e.g. silylating agents), thus decreasing the atom efficiency of the process.
Most asymmetric versions of the aldol reaction reported to date rely upon the use of chiral auxiliaries (Seyden-Penne, 1995). Mukaiyama-type processes using asymmetric catalysts have also been reported (Johnson et al., 2000; Carreira, 1998; Mahrwald, 1999; Grxc3x6ger et al., 1998; Nelson, 1998; Bach, 1994); as noted above, these require prior stoichiometric formation of the nucleophile. Methods for direct catalytic asymmetric aldol addition, without prior stoichiometric formation of the nucleophile, are thus being sought. Processes employing both biological-type (e.g. catalytic antibodies) (Machajewski et al., 2000; Takayama et al., 1997; Hoffman et al., 1998) and non-biological-type (Yoshikawa et al., 1999; Shibasaki et al., 1999; List et al., 2000; Notz et al., 2000; Agami et al., 1987; Nakayawa et al., 1985) catalysis have been reported. In all of these cases, however, significant excesses of the donor and/or large amounts of catalyst must be employed, and unbranched aldehyde substrates remain problematic.
The Henry (nitro-aldol) reaction (see e.g. Luzzio et al.) is also a fundamental Cxe2x80x94C bond forming reaction which generates stereogenic centers. There are very few examples to date of catalytic asymmetric nitroaldol reactions. Shibasaki et al. have carried out such reactions using chiral heterobimetallic (rare earth-alkali metal) catalysts, and Jorgensen et al. have reported the catalytic asymmetric aza-Henry reaction of silyl nitronates with imines. However, the use of silyl nitronates as nucleophiles undermines the atom economy of the reaction.
The present invention includes, in one aspect, a method of conducting an enantioselective aldol reaction between an aldehyde and a donor molecule selected from a nitroalkyl compound and a ketone bearing an xcex1-hydrogen, the method comprising:
contacting the aldehyde and donor compound in the presence of a catalytic amount of an asymmetric catalyst, wherein the catalyst is a complex of a Group 2A or Group 2B metal with a chiral ligand of formula I: 
where
R1-R4 are aryl groups, which may be the same or different, each of which is unsubstituted or substituted with one or more substituents X, where each X is independently selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- or aryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen,
and wherein R1 and R2, or R3 and R4, or both of these combinations, may be linked at an xcex1-carbon of each the group to form a tricyclic or larger ring system;
m is an integer from 0 to 3, is preferably 1 or 3, and is more preferably 1;
each of R5 and R6 represents one or more substituents independently selected from the group consisting of hydrogen and X as defined above; and
R7 represents one or more substituents on the phenyl ring independently selected from the group consisting of hydrogen, X as defined above, and a further fused ring;
under conditions effective to produce an aldol reaction product which is enriched in one of the possible stereoisomeric products of such reaction.
In selected embodiments, the Group 2A or Group 2B metal is Zn, Cd, Mg, Ca, or Ba. Preferably, the metal is zinc.
In additional embodiments, each of R1-R4 is phenyl or naphthyl (xcex1 or xcex2), unsubstituted or substituted with a group selected from X as defined above. In preferred embodiments, each of R1-R4 is phenyl or naphthyl (xcex1 or xcex2), unsubstituted or substituted with lower alkyl, lower alkoxy, or halogen. In additional preferred embodiments, each of R5 and R6 is hydrogen.
In further embodiments, each substituent R7 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl, aryloxy, lower alkoxy, and halogen.
In carrying out the reaction, the donor compound and aldehyde are typically present in a molar ratio between about 1:1 and 10:1. The amount of catalytic complex is preferably about 2.5 to 10 mole percent relative to moles of aldehyde. When the donor compound is an xcex1-hydroxyketone, the molar ratio is preferably between about 1:1 and 1.5:1, and the amount of catalytic complex is preferably about 2.5 to 5 mole percent. When the donor compound is a nitroalkyl compound, the molar ratio is preferably about 5:1 to 10:1.
In another aspect, the invention provides a catalytic composition consisting of a complex of a Group 2A or Group 2B metal with a chiral ligand of formula I, as defined above. The Group 2A or Group 2B metal is preferably selected from Zn, Cd, Mg, Ca, and Ba, and is most preferably zinc. Selected embodiments of the chiral ligand are described above. Exemplary chiral ligands include ligands 1a-1n, and preferably ligands, 1a, 1c-d, and 1m, as disclosed herein.
The invention also encompasses a catalytic composition formed by contacting, in a suitable solvent, a chiral ligand of formula I, as defined above, with a Group 2A or Group 2B metal compound which is capable of generating a metal alkoxide upon reaction with an alcohol. The compound may be, for example, a dialkyl metal, dialkoxy metal, alkyl metal halide, alkyl (dialkylamino) metal, or alkyl (diarylamino) metal. The metal is preferably selected from Zn, Cd, Mg, Ca, and Ba, and is most preferably zinc. In selected embodiments, the metal compound is a di(lower alkyl) zinc compound. Selected embodiments of the chiral ligand are described above.
In addition, the invention provides a chiral ligand of formula I: 
where
R1-R4 are aryl groups, which may be the same or different, each of which is unsubstituted or substituted with one or more substituents X, where each X is independently selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- or aryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen,
wherein R1 and R2, or R3 and R4, or both of these combinations, may be linked at an xcex1-carbon of each the group to form a tricyclic or larger ring system;
m is an integer from 0 to 3;
each of R5 and R6 represents one or more substituents independently selected from the group consisting of hydrogen and X as defined above; and
R7 represents one or more substituents on the phenyl ring independently selected from the group consisting of hydrogen, X as defined above, and a further fused ring.
In groups R1 to R4, the substituents defined as group X are preferably selected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy, ester, amide, sulfonamide, alkyl- or arylsulfonyl, nitro, and halogen; more preferably selected from alkyl, alkenyl, alkoxy, nitro, and halogen; and most preferably selected from lower alkyl, lower alkoxy, and halogen. In one embodiment, each of groups R1-R4 is phenyl, unsubstituted or substituted with a group selected from X above, preferably selected from lower alkyl, lower alkoxy, and halogen. In specific embodiments, R1-R4 are identical and each is unsubstituted phenyl, xcex1- or xcex2-naphthyl, or p-methoxyphenyl.
The value of m is preferably 1 or 3, and most preferably 1. R5 and R6 are preferably selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, and aryl. Each group R5 and R6 is preferably hydrogen. In another preferred embodiment, the nitrogen heterocycles are substituted such that chiral centers are not formed; i.e. by having two identical substituents at a given position, as in a gem-dimethyl group.
The substituents defined as group X for R7 are preferably selected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy, ester, amide, sulfonamide, alkyl- or arylsulfonyl, nitro, and halogen; and more preferably selected from alkyl, alkenyl, alkoxy, aryl, aralkyl, aryloxy, and halogen.
Representative ligands include compounds 1a-1n, shown in FIG. 1. In selected embodiments, the chiral ligand is selected from the group consisting of ligands 1a, 1c-d, and 1m.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.